REVIEW published: 19 May 2015 doi: 10.3389/fimmu.2015.00252 Manipulating autophagic processes in autoimmune diseases: a special focus on modulating chaperone-mediated autophagy, an emerging therapeutic target Fengjuan Wang 1 and Sylviane Muller 1,2* 1 Immunopathology and Therapeutic Chemistry/Laboratory of Excellence MEDALIS, CNRS, Institut de Biologie Moléculaire et Cellulaire, Strasbourg, France, 2 University of Strasbourg Institute for Advanced Study, Strasbourg, France Autophagy, a constitutive intracellular degradation pathway, displays essential role in the homeostasis of immune cells, antigen processing and presentation, and many other immune processes. Perturbation of autophagy has been shown to be related to several autoimmune syndromes, including systemic lupus erythematosus. Therefore, modulating Edited by: autophagy processes appears most promising for therapy of such autoimmune diseases. Stephanie Hugues, Université de Genève, Suisse Autophagy can be said non-selective or selective; it is classified into three main forms, Reviewed by: namely macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA), Xinjian Chen, the former process being by far the most intensively investigated. The role of CMA remains University of Utah, USA Willem Van Eden, largely underappreciated in autoimmune diseases, even though CMA has been claimed Utrecht University, Netherlands to play pivotal functions into major histocompatibility complex class II-mediated antigen *Correspondence: processing and presentation. Therefore, hereby, we give a special focus on CMA as Sylviane Muller, a therapeutic target in autoimmune diseases, based in particular on our most recent UPR3572 CNRS, Institut de Biologie Moléculaire et Cellulaire, experimental results where a phosphopeptide modulates lupus disease by interacting Immunopathologie et Chimie with CMA regulators. We propose that specifically targeting lysosomes and lysosomal Thérapeutique, 15 Rue René Descartes, Strasbourg 67000, France pathways, which are central in autophagy processes and seem to be altered in certain [email protected] autoimmune diseases such as lupus, could be an innovative approach of efficient and personalized treatment. Specialty section: This article was submitted to Antigen Keywords: chaperone-mediated autophagy, antigen MHCII presentation, systemic lupus erythematosus, autoim- Presenting Cell Biology, a section of mune diseases, lysosomal dysfunction, P140 peptide/Lupuzor the journal Frontiers in Immunology Received: 02 April 2015 Introduction Accepted: 07 May 2015 Published: 19 May 2015 Autophagy, an intracellular degradation pathway in which lysosomes play a central role, has been Citation: raised as a hot topic in almost every aspect of cellular processes, including immune responses Wang F and Muller S (2015) and regulation. As it could be expected, therefore, any alteration of autophagy processes can Manipulating autophagic processes in potentially affect the normal course of cell metabolism and give rise to more or less dramatic autoimmune diseases: a special focus cell malfunctioning. It is precisely what is more and more often emerging from experimental on modulating chaperone-mediated studies. Nowadays, there is growing evidence reporting the implication of autophagy alteration autophagy, an emerging therapeutic target. in a variety of pathological indications. In particular, some autophagy failures have been sug- Front. Immunol. 6:252. gested or experimentally demonstrated in situation of chronic inflammation and autoimmune doi: 10.3389/fimmu.2015.00252 diseases. Frontiers in Immunology | www.frontiersin.org 1 May 2015 | Volume 6 | Article 252 Wang and Muller Autophagy and therapy of autoimmune diseases Antigen presentation is a vital step in immune regulation showing that in fact macroautophagy participates in a highly selec- where antigen-presenting cells (APCs) process antigens into short tive and tightly regulated process of substrate delivery (20–22). peptides, which are then loaded in to major histocompatibil- Direct evidence has been reported that endogenous antigen pre- ity complex (MHC) class I (MHCI) and II (MHCII) molecules sentation depends on macroautophagy (3, 23–26), and activation and presented in this context to T cells. Classical (professional) of macroautophagy could facilitate presentation of intracellular APCs include dendritic cells (DCs), macrophages, Langerhans peptide on MHCII molecules (2). In DCs used as APCs, the cells (LCs), and B cells. Beside this canonical antigen presentation autophagy-related gene (ATG) 5, a key autophagy gene, seems to pathway, DCs and non-APCs can acquire MHCI and/or MHCII be required for antigen presentation (26). While mice with DC- molecules from neighboring cells through a pathway of cell–cell conditional deletion in Atg5 displayed no development defect, contact-dependent membrane transfer called trogocytosis. These they showed, however, important failure mounting a normal so-called “MHC-dressed cells” subsequently activate or regulate T T-cell response linked to improper processing and presentation cells via peptide–MHC complexes without requiring any further of cytosolic antigens on MHCII molecules. processing (1). Exosome-mediated transfer might also contribute The third main type of autophagy, CMA (Figure 1), is a to this process. process where client proteins containing specific motifs related Cells use a variety of mechanisms to generate antigens that will to KFERQ (present in about 30% of soluble cytosolic proteins) be presented in the context of MHC molecules to the receptor (27) are selectively recognized by the cytosolic chaperone pro- of T cells (TCR). Among these pathways, autophagy is consid- tein HSPA8/HSC70 present in a co-chaperones-rich complex that ered a major process for the delivery of cytosolic and nuclear delivers them to the lysosome membrane. Examples of such client antigens to MHCII molecules in mature or late endosomes, also proteins/substrates are glyceraldehyde 3-phosphate dehydroge- known as MIIC compartments (2–7). Abnormalities in antigen nase, the E3 ubiquitin ligase ITCH, the calcineurin inhibitor presentation have been proposed to play an important role in RCAN1, the neuronal alpha-synuclein and tau proteins, galectin- autoimmune diseases. In systemic lupus erythematosus (SLE), for 3, and HSPA8 (28–30). The complex containing HSPA8 associated example, hyperactivity of T cells resulting from panoply of factors to the substrate then binds to the so-called lysosomal-associated might be related to abnormal antigen presentation by APCs (8, membrane protein type 2A (LAMP-2A), acting as a monomer at 9). Control of the autophagy pathway is thus critical, and phar- this stage. LAMP-2A (but not LAMP-2B or LAMP-2C, or HSPA8) macological intervention targeting specific steps of this complex is exclusive for CMA. The binding of substrates to LAMP-2A leads process could be determining at reprograming some dysfunction to its multimerization, likely with the help of lysosomal HSP90 of the immune system occurring notably in inflammatory and protein; the substrates undergo unfolding and reach the lysosome autoimmune diseases (10–16). lumen through the LAMP-2A-enriched translocation complex Three major forms of autophagy have been found ubiquitously with the aid of lysosomal HSPA8, where they are degraded by in eukaryotic cells, namely microautophagy, macroautophagy, lysosomal proteases. LAMP-2A multimers then disassemble and and chaperone-mediated autophagy (CMA). Microautophagy is degrade for the next cycle of CMA (28). This process, which featured by a direct engulfment of cytosolic portions through is finely regulated (29), is carried out at basal level and can be lysosomal invagination. It is the least studied process among the activated under prolonged starvation and other stresses. It works three processes, yet microautophagy-like process has been shown then as an alternative energy sources and quality control to remove to deliver cytosolic proteins to late endosomal compartments in damaged proteins upon stress. CMA dysfunction (enhancement DCs and might represent an important alternative route for anti- or slowdown) seems to directly or indirectly contribute in many gen presentation (17, 18). This microautophagy-like degradation diseases including neurodegenerative pathologies, metabolic dis- pathway does not depend on the canonical autophagy machinery eases, and cancer (31–34). Recent evidences from our laboratory and is distinct from CMA. and others strongly support the importance of CMA in antigen Macroautophagy is the most intensively studied form of presentation and pathological conditions, especially in autoim- autophagy and the vast majority of currently published data on the munity. role of autophagy in antigen presentation result from investigation The role of macroautophagy in antigen presentation has been based on this basic autophagic process. In the macroautophagy described extensively in comprehensive reviews (7, 16, 35–41). pathway (Figure 1), double-membrane structures are generated Original data also accumulated supporting a central role for to engulf whole cytosolic components, including organelles, and macroautophagy in both innate and adaptive immune responses, form autophagosomes. The latter then use microtubular tracks which greatly influence antigen presentation (42–45). Our inten- to encounter and fuse with lysosomes/late endosomes to form tion herein is therefore to orientate our discussion on recent vesicles called autolysosomes